The Neurodegenerative Diseases Research Unit (NDRU) focuses on atypical parkinsonism syndromes. Our mission is to unravel molecular genetic mechanisms involved in the pathophysiology of parkinsonism, to study molecular relationships between common neurodegenerative diseases and to discover targets for rational therapeutic development. NDRU is highly collaborative and data-driven, combining interdisciplinary clinical and genomic research to improve knowledge about parkinsonism syndromes. Over the last year, we sought to test the hypothesis that known, high-risk neurodegenerative disease alleles may alter risk for developing atypical parkinsonism syndromes. For example, we assessed APOE in cohorts with atypical parkinsonism syndromes. Similar to observations made in Alzheimers disease, we found that patients carrying the 4 allele have an increased risk for Lewy body dementia, while individuals with 2 alleles have a decreased disease risk. In addition, we demonstrated that carrying the APOE 4 allele decreases survival in a dose-dependent manner. No associations with disease were observed in progressive supranuclear palsy, corticobasal syndromes, and multiple system atrophy. Along the same lines, as part of a multicenter collaboration, a mutation in the PLCG2 gene was examined for association with neurodegenerative dementia syndromes, including Alzheimers disease, Lewy body dementia, and frontotemporal dementia. The study found a protective effect of this coding mutation that increased longevity in all three neurodegenerative dementias. This intriguing finding might be of interest for future therapeutic development. Next-generation sequencing applications commonly identify novel, rare variants in known neurodegenerative disease genes. The role of these variants in neurological disease can be quite difficult to interpret and requires thoughtful assessments in well-defined, large cohorts. In the last year, we examined several interesting variants in parkinsonism cohorts to better delineate their role in neurodegenerative diseases (e.g. p.V363I mutation in the gene MAPT in corticobasal degeneration, loss of function variants in LRRK2 in Parkinsons disease, LRP10 mutations in synucleinopathies, and others). We will continue to evaluate promising mutations in disease genes to increase our understanding of rare genetic changes and to improve counseling of patients carrying these variants. Using unbiased, genome-wide association study approaches, we have been part of several studies that discovered novel risk genes implicated in Lewy body dementia, amyotrophic lateral sclerosis and Parkinson's disease. We will continue to carry out important gene identification studies to improve our understanding of the molecular mechanisms that drive neurodegenerative syndromes. This knowledge might be leveraged in future therapeutic development efforts. Genome sequencing offers unprecedented opportunities to study the molecular underpinnings driving disease risk. NDRU is a leading member of an ambitious, intramural genome-sequencing initiative that generated a unique resource for dementia research. Specifically, we produced genome sequence data of 3,000 Lewy body dementia cases, 3,000 frontotemporal dementia cases, and 2,000 neurologically healthy controls. The overall aim of this project is to expand genetic discovery efforts to non-Alzheimer dementias and to accelerate the pace of discovery in these underserved diseases by making the data available to the research community. In summary, NDRU has taken full advantage of the unique opportunities and resources within the Intramural Research Program. We have already gained valuable insights into the molecular underpinnings in complex neurodegenerative diseases and will continue to apply modern genomic approaches to yield actionable data for advancing understanding and clinical approaches toward parkinsonism syndromes.